Our goal is to identify functional variants in the ACACA (acetyl coenzyme A carboxylase-alpha) gene that protect against human obesity. Obesity is a highly heritable trait and a risk factor for type 2 diabetes, heart disease, and hypertension that contributes to approximately 300,000 premature deaths in the United States annually. Nonetheless, the common genetic determinants of obesity and body weight are unknown. We performed a dense whole-genome scan of 1327 participants from the Framingham Heart Study Cohort (FHS) at a density of 100,000 SNPs per individual and analyzed the data using a novel analysis strategy that we helped develop for family-based association studies. We found that common genetic variation near the INSIG2 gene (insulin-induced gene 2) is associated with obesity. In this proposal we describe new results showing that common genetic variation in another gene in the same pathway as INSIG2, the ACACA gene that encodes ACC1, is associated with lower body mass index. We describe replication of the association in an African-American population from the Howard University Family Study (HUFS). ACC1 and INSIG2 are in the SREBP-dependent pathway of fatty acid and cholesterol synthesis defined by the pioneering work of Brown and Goldstein. The ACC1-T or "thinness" predisposing genotype is present in ~3% of individuals from FHS and 10% of individuals from HUFS. Interestingly, ACACB knockout mice are also resistant to diet-induced obesity. Our study supports the common disease/common variant hypothesis and demonstrates the important role of common genetic factors and the SREBP pathway in obesity and body weight regulation in general. Our hypothesis is that the ACACA haplotype associated with leanness results from diminished fatty acid synthesis reflecting a loss of ACC1 function, due either to lowered expression, differences in alternative splicing or changes in amino acid sequence of ACC1. Our goal is to identify functional genetic variations in the ACACA responsible for this loss of function to set the stage for subsequent biochemical and cell biology experiments. We will fine map the ACC-T association with BMI (body mass index) in both the Framingham Heart Study (FHS) and an African American cohort (Howard University Family Study (HUFS)) with the goal of further localizing the region containing the causative genetic variant. We will then perform directed resequencing of non-coding regions and of exons to identify functional variant(s).